Programmed cell death in cancer cells: Overcoming resistance through paraptosis-inducing compounds

Programmed cell death in cancer cells: Overcoming resistance through paraptosis-inducing compounds

12/07/2022

Apoptosis, a type of programmed cell death (PCD), is a biological process through which unwanted cells are eliminated in multicellular organisms. In most cells, certain proteins known as “caspases” trigger apoptosis. This process is especially important for the treatment of cancer, since inducing cell death in cancer cells can help in their elimination.

Other than apoptosis, several types of PCDs occur in cells, including paraptosis, necroptosis, and autophagy. Of these, paraptosis is the most recently identified type of PCD, which is caused by the influx of excess calcium in the cells, leading to cell death.

Cancer cells often become resistant to drugs that induce apoptosis and other types of PCDs. In such cases, inducing paraptosis, which is not dependent on caspases, could act as a promising anti-cancer treatment. Hence, the development of compounds that can induce paraptosis in cancer cells is crucial.

To this end, a team of researchers from the Tokyo University of Science, led by Prof. Shin Aoki in collaboration with Mr. Kohei Yamaguchi and Dr. Kenta Yokoi, conducted a study to develop novel complex-peptide hybrids with paraptosis-inducing potential. This study was made available online on 11 April 2022, and subsequently published in Volume 33 of the journalBioconjugate Chemistry, on 20 April 2022.

“Previously, we synthesized an iridium complex-peptide hybrid compound and observed that it induced cell death in cancer cells, which was different from apoptosis. Since this compound was unlike other paraptosis-inducing compounds, we wanted to understand its mechanism of paraptosis induction. Our goal now is to synthesize new compounds and elucidate how they induce paraptosis in cells, before we share this crucial information with the public,” explains Prof. Aoki while discussing the team’s motivation behind this study.

The newly synthesized compounds were composed of a triptycene core — an aromatic hydrocarbon — with two or three cationic peptides made of the amino acids lysine and glycine (represented as KKKGG) through a C8 alkyl linker chain, at different positions of the triptycene units. As a result, three triptycene core hybrids (TPHs) were produced, namely, 5, syn-6, and anti-6.

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